Drugs that have abuse liability in humans typically serve as positive reinforcers to maintain and strengthen behavior leading to their administration in animals and provoke relapse to previously extinguished drug-seeking behavior in abstinent animals. Experiments are being conducted to assess neurobiological and behavioral mechanisms underlying drug self-administration and relapse behavior rats and monkeys, and the ability of pharmacological manipulations to modify such behavior. Our previous studies suggest that electively blocking presynaptic A2A receptors could provide a new pharmacological approach to the treatment of marijuana dependence and underscore corticostriatal glutamatergic neurotransmission as a possible main mechanism involved in the rewarding effects of of the marijuana constituent delta-9-tetrahydrocannabinol (THC).Different doses of an adenosine A2A receptor antagonist MSX-3 3,7-dihydro-8-(1E)-2-(3-ethoxyphenyl)ethenyl-7 methyl-3-3-(phosphooxy)propyl-1-(2 propynil)-1H-purine-2,6-dione were found previously to either decrease or increase self-administration of the cannabinoids THC or anandamide in squirrel monkeys. It was hypothesized that the decrease observed with a relatively low dose of MSX-3 was related to blockade of striatal presynaptic A2A receptors that modulate glutamatergic neurotransmission, whereas the increase observed with a higher dose was related to blockade of postsynaptic A2A receptors localized in striatopallidal neurons. This hypothesis was confirmed in the present study by testing the effects of the preferential presynaptic and postsynaptic A2A receptor antagonists SCH-442416 2-(2-furanyl)-7-3-(4-methoxyphenyl)propyl-7H-pyrazolo4,3-e1,2,4triazolo1,5-cpyrimidin-5-amine and KW-6002 (E)-1, 3-diethyl-8-(3,4-dimethoxystyryl)-7-methyl-3,7-dihydro-1H-purine-2,6-dione, respectively, in squirrel monkeys trained to intravenously self-administer THC. SCH-442416 produced a significant shift to the right of the THC self-administration dose-response curves, consistent with antagonism of the reinforcing effects of THC. Conversely, KW-6002 produced a significant shift to the left, consistent with potentiation of the reinforcing effects of THC. These results suggest the adenosine A2A receptor as a potential target for the development of medications to treat marijuana dependence. In the reward circuitry of the brain, &#945;-7-nicotinic acetylcholine receptors (&#945;7nAChRs) modulate effects of delta-9-tetrahydrocannabinol (THC), marijuana's main psychoactive ingredient. Kynurenic acid (KYNA) is an endogenous negative allosteric modulator of &#945;7nAChRs. Here we report that the kynurenine 3-monooxygenase (KMO) inhibitor Ro 61-8048 increases brain KYNA levels and attenuates cannabinoid-induced increases in extracellular dopamine in reward-related brain areas. In the self-administration model of drug abuse, Ro 61-8048 reduced the rewarding effects of THC and the synthetic cannabinoid WIN 55,212-2 in squirrel monkeys and rats, respectively, and it also prevented relapse to drug-seeking induced by reexposure to cannabinoids or cannabinoid-associated cues. The effects of enhancing endogenous KYNA levels with Ro 61-8048 were prevented by positive allosteric modulators of &#945;7nAChRs. Despite a clear need, there are no medications approved for treatment of marijuana dependence. Modulation of KYNA offers a pharmacological strategy for achieving abstinence from marijuana and preventing relapse. Enhancing the effects of endogenously-released cannabinoid ligands in the brain might provide therapeutic effects more safely and effectively than administering drugs that act directly at the cannabinoid receptor. Inhibitors of fatty acid amide hydrolase (FAAH) prevent the breakdown of endogenous ligands for cannabinoid receptors and peroxisome proliferator-activated receptors (PPAR), prolonging and enhancing the effects of these ligands when they are naturally released. In an ongoing series of experiments we are assessing the effects of FAAH inhibitors and PPAR activators in animal models of addiction and cognition (specifically learning and memory). These studies show that FAAH inhibitors can produce potentially therapeutic effects, some through cannabinoid receptors and some through PPAR. These effects include enhancing certain forms of learning, counteracting the rewarding effects of nicotine and alcohol, relieving symptoms of withdrawal from cannabis and other drugs, and protecting against relapse-like reinstatement of drug self-administration. Since FAAH inhibition might have a wide range of therapeutic actions but might also share some of the adverse effects of cannabis, it is noteworthy that in studies we have been conducting with a series of recently developed FAAH inhibitors, several had THC-like reinforcing and relapse-inducing effects but two selective FAAH inhibitors, URB597 and URB694, had potentially beneficial effects in animal models of nicotine dependence but no indication of reinforcing or relapse-inducing effects. Our research is ongoing but the preliminary evidence indicates that these FAAH inhibitors might lead to improved therapeutic interventions in nicotine dependence and a better understanding of the brain mechanisms underlying nicotine dependence.